Glutamatergic transmission has proved elusive to study in vivo, in human subjects, with sensitive radionuclide-based imaging techniques such as positron emission tomography (PET). Because of the importance of glutamatergic transmission in various neuropsychiatric disorders as well as its modulatory effect on other transmitter systems, we have embarked upon a program to develop imaging agents for glutamate carboxypeptidase II (GCPII), an enzyme within the brain that cleaves Nacetylaspartylglutamate (NAAG), to the glutamatergic transmitters N-acetylaspartate and glutamate. GCPII is a transmembrane enzyme with the active site external to the cell, thereby providing an excellent imaging target. GCPII inhibition has been pursued in the context of treating cerebral ischemia and chronic pain and abnormality of GCPII activity has been described in schizophrenia, further underscoring the rationale for imaging this target. GCPII has been designated as the "brain prostate-specific membrane antigen (PSMA)" because of the NAAG-peptidase activity of PSMA. GCPII and PSMA share nearly identical pharmacological profiles. As an extension of our effort to develop small molecule, PSMA-based imaging agents for prostate cancer, we propose to synthesize a series of lipophilic GCPII ligands for imaging this enzyme in the brain. Those new compounds will be patterned after the urea-based ligands that we have already made to image prostate cancer. The synthesis, in vitro and in vivo (animal) evaluation of those compounds will occur during the first two years (R21 phase). The R33 phase will consist of one year dedicated to obtaining appropriate dosimetry and toxicology data as well as preparation of a physician-sponsored investigational new drug application to the FDA for a pilot study of the best compound(s) in human subjects. We intend to use a portion of the R33 phase for refinement of the human imaging protocol and radiotracer kinetic models for future studies in schizophrenia and other neuropsychiatric conditions. Working with our knowledge of PSMA/GCPII imaging and the recently published crystal structure of PSMA, we intend to pursue new derivatives suitable for imaging GCPII within the central nervous system